Familial hypocalciuric hypercalcaemia (FHH) is a disorder that is inherited in an autosomal dominant fashion in which affected individuals have abnormally high concentrations of serum calcium and excrete inappropriately low amounts of urinary calcium. We hypothesize that affected individuals with this disorder regulate calcium in an abnormal fashion and that understanding this perturbed mechanism of calcium regulation will provide important information both about this disorder and the normal mechanism of calcium homeostasis. The patterns of inheritance of this disorder suggest that a mutation(s) in a single gene is responsible for FHH, and we propose to identify this gene by molecular genetic techniques that have been used to identify other genes that when mutated cause disease. Although these techniques require significant effort, the benefits of identifying the precise gene and the mutation(s) responsible for a particular disorder make this effort worthwhile. The long term goals of the proposed studies are to identify the gene(s) that is mutated in FHH patients and to determine the genetic relationship of FHH to another disorder of calcium regulation, neonatal severe hyperparathyroidism (NSHPT). We will take the following approaches to identify the mutation(s) responsible for FHH. 1) Determine if FHH is a genetically heterogeneous or homogeneous disorder and refine the genetic map in the FHH region(s); 2) Refine the physical map in the FHH-1 region; 3) Search the FHH region of chromosome 3 for gene segments; 4) Identify candidate genes and determine if they are mutated in FHH subjects; and 5) Determine if NSHPT results from homozygous deficiencies at the FHH-1 locus.